Amyotrophic lateral sclerosis (ALS) is an enigmatic, horrific illness with a rapid course of progression for which there is little in the way of effective therapy. Finding objective markers for the progression of the disease is crucial for assessing the efficacy of proposed therapies and etiologic mechanisms. Magnetic resonance imaging (MRI) and spectroscopy (MRS) offer many potential markers that may be of great value in following the natural history and onset of ALS symptoms. We specifically propose to longitudinally follow the onset and progression of symptoms in a transgenic rat model of ALS. We will measure neurochemical markers of metabolism and neuronal health using MRS of motor cortex, medulla and spinal cord, and evaluate spinal cord morphometry using MRI. We also develop and test a novel tool for evaluation of motor circuitry that would be directly applicable to human subjects with limited movement. This tool involves the use of passive stimulation consequent to administration of amphetamine and monitoring the activation of dopaminergic and glutamatergic motor circuitry. It represents a high-risk, high-reward concept for characterization of the symptomatic progression of ALS that is not confounded with performance issues that bedevil task-related motor studies using fMRI of later stage ALS subjects. The MRI and MRS data will be correlated with objective measurements of motor symptoms as well as histological markers of neuronal loss and survival data in a well-controlled systematic study. These studies should lead to three primary outcomes: better markers for diagnosing and following ALS symptoms;better understanding of the meaning of the neurochemical markers in the context of ALS pathology, and better understanding the regional progression and degeneration of the motor circuitry in ALS. PUBLIC HEALTH RELEVANCE This project will develop and apply non-invasive markers for evaluation of the onset and progression of disease in a rodent model of amyotrophic lateral sclerosis (ALS) by utilizing MRS and MRI. The results should lead to a set of markers to better quantify disease diagnosis and progression that will be directly applicable to human studies of the natural history and therapy of this devastating disease.